EP0322391A1 - Nouveaux dérivés de la phénylalkylamine - Google Patents

Nouveaux dérivés de la phénylalkylamine Download PDF

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Publication number
EP0322391A1
EP0322391A1 EP88850429A EP88850429A EP0322391A1 EP 0322391 A1 EP0322391 A1 EP 0322391A1 EP 88850429 A EP88850429 A EP 88850429A EP 88850429 A EP88850429 A EP 88850429A EP 0322391 A1 EP0322391 A1 EP 0322391A1
Authority
EP
European Patent Office
Prior art keywords
compound
hydrogen
process according
defined above
prepared
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Granted
Application number
EP88850429A
Other languages
German (de)
English (en)
Other versions
EP0322391B1 (fr
Inventor
Lars Ivar Gawell
Gerd Margareta Hallnemo
Thomas Högberg
Ulf Henrik Anders Lindberg
Hans Eric Peter Ström
Carl Bengt Johan Ulff
Christina Elizabeth Akesson
Sven Ove Ögren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AstraZeneca AB
Original Assignee
Astra AB
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from SE8705089A external-priority patent/SE8705089D0/xx
Application filed by Astra AB filed Critical Astra AB
Priority to AT88850429T priority Critical patent/ATE73993T1/de
Publication of EP0322391A1 publication Critical patent/EP0322391A1/fr
Application granted granted Critical
Publication of EP0322391B1 publication Critical patent/EP0322391B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C221/00—Preparation of compounds containing amino groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/22—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated
    • C07C215/28—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C225/00—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones
    • C07C225/02—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C225/14—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated
    • C07C225/16—Compounds containing amino groups and doubly—bound oxygen atoms bound to the same carbon skeleton, at least one of the doubly—bound oxygen atoms not being part of a —CHO group, e.g. amino ketones having amino groups bound to acyclic carbon atoms of the carbon skeleton the carbon skeleton being unsaturated and containing six-membered aromatic rings

Definitions

  • the object of the present invention is to provide novel compounds and therapeutically acceptable salts thereof with a potentiating effect on cholinergic responses.
  • This invention also relates to processes for the preparation of the new compounds as well as to the pharmacological use of the new compounds and to pharmaceutical preparations containing such compounds.
  • n 0 or 1
  • Z is CO or CH(OH)
  • R1 and R2 are equal or different and, when equal, hydrogen, methyl, ethyl or propyl and, when different, R1 is hydrogen and R2 is methyl, ethyl, propyl or isopropyl
  • X and Y represent hydrogen, halogen, CF3, CN or an alkyl group, straight or branched having 1-3 carbon atoms, in the ortho, meta or para position provided that when X is in the ortho position and other than hydrogen then Y is other than hydrogen, and when Y is in the ortho position and other than hydrogen then X is other than hydrogen
  • R represents a straight or branched saturated or unsaturated 1-6 carbon alkyl group, a 3-6 carbon cycloalkyl group, a phenyl group, which may be unsubstituted or may carry a ring substituent X1, X1 preferably being
  • R is, when alkyl, preferably saturated straight or branched having 1-3 carbon atoms in the chain.
  • R has, when cycloalkyl, preferably 5-6 carbon atoms in the ring.
  • X, Y and X1 are preferably in the meta and/or para positions.
  • Halogen X, Y and X1 is preferably bromo, chloro or fluoro in the meta and/or para positions and in particular in the para position when being the monosubstituent. Most preferred is para fluoro.
  • X and/or Y is CF3 it is preferably in the meta position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
  • X and/or Y is CN it is preferably in the para position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
  • X and/or Y is alkyl it is preferably methyl in the para position when being the monosubstituent, and in particular when R is a saturated alkyl group straight or branched having 1-3 carbon atoms in the chain.
  • the invention relates to new compounds of the general formula Ia, wherein Z is CO or CH(OH), X is halogen and R is a straight or branched alkyl group having 1-5 carbon atoms in the chain in racemic or optically active form, and when Z is CH(OH) also mixtures of diastereomers or the pure diastereomers, with the proviso that the racemate of the compound, wherein X is Cl, Z is CO and R is methyl is excluded; or pharmaceutically acceptable salts thereof.
  • halogen is preferably chloro or fluoro and R is preferably an ethyl or isopropyl group.
  • the compounds of the invention potentiate transmittor responses, probably by the modulation of ion-channels coupled to various neurotransmittor receptors. These effects makes it possible to use the compounds in the treatment of mental disturbances e.g. psychosis, schizophrenia, schizoaffective conditions, anxiety, unipolar and bipolar depression as well as in the treatment of minimal memory impairment (MMI) and of senile dementia of the Alzheimer type (SDAT).
  • MMI minimal memory impairment
  • SDAT senile dementia of the Alzheimer type
  • certain compounds have a potentiating effect on central cholinergic responses. This potentiation is probably mediated by effects on ion channels, most likely of the potassium type. The latter two disturbances, MMI and SDAT, are believed to be associated with cholinergic dysfunction.
  • the reducing agent is preferably sodium cyanoborohydride, sodium borohydride, or hydrogen in the presence of a catalyst e.g. Pd/C, Pt or Raney Ni. It is especially preferred to perform the reaction in methanol with sodium cyanoborohydride as reducing agent.
  • the reducing agent is an appropriate reagent preferably chosen from the following: Sodium in liquid ammonia or lithium in an amine solution in the presence of an alcohol, or hydrogen in the presence of a catalyst,or lithium aluminium hydride or sodium borohydride in the presence of a Lewis acid. Most preferred is sodium in liquid ammonia in the presence of t-butanol for the preparation of compound I when Z is CO, and lithium aluminium hydride for the preparation of compound I when Z is CH(OH).
  • the group Y1 in the compound V may be chosen from easily cleaved, chiral or nonchiral amides, carbamates, imines, benzylic amines or other suitable amine protecting groups. Such groups can be trifluoroacetamide, formamide, t-butylcarbamate, N-benzylamine, (S) or (R)-­phenethylamine, or chiral Schiff bases such as (+) or (-)-2-­hydroxypinanyl-3-indeneamines.
  • Y1 can be groups such as nitro, azido, oxime, hydrazone or imine, which can be transformed to NH2 by known reductive processes.
  • Y1 can be NR1R2 when R1 and/or R2 is hydrogen, which can be alkylated by known processes in a stepwise or direct manner.
  • the compounds of the formula II can be isolated as such and subsequently converted to a compound of the formula I or the compounds of the formula II can be generated in situ and converted to a compound of the formula I without isolation.
  • the group R may be an unsaturated alkyl or a suitable protected alkyn.
  • the compounds of the formula I will normally be administered orally, rectally or by injection, in the form of pharmaceutical preparations comprising the active ingredient either as a free base or a pharmaceutically acceptable non-toxic, acid addition salt, e.g. the hydrochloride, hydrobromide, lactate, acetate, phosphate, sulphate, sulphamate, citrate, tartrate, oxalate and the like in association with a pharmaceutically acceptable dosage form.
  • the dosage form may be a solid, semisolid or liquid preparation.
  • the active substance will constitute between 0.1 and 99% by weight of the preparation, more specifically between 0.5 and 20% by weight for preparations intended for injection and between 0.2 and 50% by weight for preparations suitable for oral administration.
  • the selected compound may be mixed with a solid excipient, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, e.g.
  • the tablet can be coated with a polymer known to the man in the art, dissolved in a readily volatile organic solvent or mixture of organic solvents or in water. Dyestuffs may be added to these coatings in order to readily distinguish between tablets containing different active substances or different amounts of the active compounds.
  • the active substance may be admixed with e.g. a vegetable oil or polyethylene glycol.
  • Hard gelatine capsules may contain granules of the active substance using either the above mentioned excipients for tablets e.g. lactose, saccharose, sorbitol, mannitol, starches (e.g. potato starch, corn starch or amylopectin), cellulose derivatives or gelatine. Also liquids or semisolids of the drug can be filled into hard gelatine capsules.
  • Dosage units for rectal application can be solutions or suspensions or can be prepared in the form of suppositories comprising the active substance in admixture with a neutral fatty base, or gelatine rectal capsules comprising the active substance in admixture with vegetable oil or paraffin oil.
  • Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing from about 0.2 % to about 20 % by weight of the active substance herein described, the balance being sugar and mixture of ethanol, water, glycerol, and propylene glycol.
  • Such liquid preparations may contain colouring agents, flavouring agents, saccarine and carboxymethylcellulose as a thickening agent or other excipients known to the man in the art.
  • Solutions for parenteral applications can be prepared in an aqueous solution of a water-soluble pharmaceutically acceptable salt of the active substance preferably in a concentration of from about 0.5 % to about 10 % by weight. These solutions may also contain stabilizing agents and/or buffering agents and may conveniently be provided in various dosage unit ampoules.
  • Suitable daily doses of the compounds of the invention in therapeutical treatment of humans are 100 to 500 mg at peroral administration and 20 to 100 mg at parenteral administration.
  • the compounds according to the invention are characterized by standard spectroscopic techniques, e.g. 1H NMR and 13C NMR. Data are given in the following Tables 1 and 2. All data except for Example 9 are related to the respective base. For Example 9 the salt has been used.
  • compositions 1 000 tablets can be made, containing 50 mg and 100 mg of active substance, respectively. If desired, the obtained tablets can be film coated with e.g. methyl cellulose in an organic solvent or using water.
  • Example of solution for intravenous or intramuscular injection Compound according to Example 1 60 g Water for injection ad 1000 ml
  • the active compound shall be dissolved in water to a final volume of 1000 ml and the solution filtered through a sterile 0.22 ⁇ m filter and aseptically dispensed into 1 ml sterile ampoules, which then are sealed.
  • mice Male rats (Sprague Dawley Alab Laboratorietjänst AB, Sollentuna, Sweden) weighing 150-180 g, 35-40 days of age, were used. The animals were allowed free access to food (R3, Ewos AB, Södertälje, Sweden) and water until the start of the experiments. The test compounds were injected intraperitoneally (i.p.) 30 minutes before injection of the muscarine agonist oxotremorine (OTM) into the neck (s.c.). Tremor intensity was assessed visually for a 60 minutes period following the injection of OTMN in rat housed in Macrolon cages (25x25x30 cm) (three per cage). The threshold dose of OTMN for eliciting tremor in rat is about 200 ⁇ g/kg.
  • OTMN oxotremorine
  • the compounds of the general formula I potently potentiate the tremor inducing effect of oxotremorine, which indicates a facilitation of central cholinergic responses.

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Psychiatry (AREA)
  • Hospice & Palliative Care (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Steroid Compounds (AREA)
  • Jib Cranes (AREA)
  • Superconductors And Manufacturing Methods Therefor (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
EP88850429A 1987-12-21 1988-12-20 Nouveaux dérivés de la phénylalkylamine Expired - Lifetime EP0322391B1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AT88850429T ATE73993T1 (de) 1987-12-21 1988-12-20 Neue phenylalkylamin-derivate.

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE8705089A SE8705089D0 (sv) 1987-12-21 1987-12-21 New compounds
SE8705089 1987-12-21
SE8804277 1988-11-25
SE8804277 1988-11-25

Publications (2)

Publication Number Publication Date
EP0322391A1 true EP0322391A1 (fr) 1989-06-28
EP0322391B1 EP0322391B1 (fr) 1992-03-25

Family

ID=26660072

Family Applications (1)

Application Number Title Priority Date Filing Date
EP88850429A Expired - Lifetime EP0322391B1 (fr) 1987-12-21 1988-12-20 Nouveaux dérivés de la phénylalkylamine

Country Status (25)

Country Link
EP (1) EP0322391B1 (fr)
JP (1) JPH02240A (fr)
KR (1) KR890009848A (fr)
CN (1) CN1023478C (fr)
AT (1) ATE73993T1 (fr)
AU (1) AU611978B2 (fr)
DE (1) DE3869583D1 (fr)
DK (1) DK713088A (fr)
EG (1) EG18654A (fr)
ES (1) ES2033013T3 (fr)
FI (1) FI885905A (fr)
GR (1) GR3004617T3 (fr)
HU (1) HU204765B (fr)
IE (1) IE61133B1 (fr)
IL (1) IL88641A (fr)
IS (1) IS1556B (fr)
LV (1) LV10244A (fr)
MY (1) MY104117A (fr)
NO (1) NO169837C (fr)
NZ (1) NZ227299A (fr)
PL (3) PL161564B1 (fr)
PT (1) PT89272B (fr)
RU (1) RU1836331C (fr)
SU (1) SU1750418A3 (fr)
YU (3) YU231888A (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014726A1 (fr) * 1991-02-23 1992-09-03 Bayer Aktiengesellschaft Pyridylpyrimidines substituees, leur preparation et leur utilisation, ainsi que nouveaux intermediaires
WO1995011224A1 (fr) * 1993-10-22 1995-04-27 Abbott Laboratories Procedes de preparation d'un 2,5-diamino-3-hydroxyhexane substitue

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100769320B1 (ko) * 2007-08-07 2007-10-24 태 봉 김 사격장 탄두회수장치

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4177291A (en) * 1976-08-25 1979-12-04 Astra Lakemedel Aktiebolag Compounds having antidepressive activity
US4469707A (en) * 1983-04-29 1984-09-04 Astra Lakemedel Aktiebolag Method for treatment of senile dementia

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4177291A (en) * 1976-08-25 1979-12-04 Astra Lakemedel Aktiebolag Compounds having antidepressive activity
US4469707A (en) * 1983-04-29 1984-09-04 Astra Lakemedel Aktiebolag Method for treatment of senile dementia

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Eur. J. Med. Chem.-Chimica Therapeutica November-December 1981-16, No 6, pages 495-501, U.H. LINDBERG et al: "Inhibitors of Neuronal Monoamine Uptake III. Synthesis and Pharmacologic Screening of Alaproclate Analogues", * see the whole document * *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992014726A1 (fr) * 1991-02-23 1992-09-03 Bayer Aktiengesellschaft Pyridylpyrimidines substituees, leur preparation et leur utilisation, ainsi que nouveaux intermediaires
US5416088A (en) * 1991-02-23 1995-05-16 Bayer Aktiengesellschaft Substituted pyridylpyrimidines, their preparation and their use
US5502233A (en) * 1991-02-23 1996-03-26 Bayer Aktiengesellschaft Enamine intermediates for the preparation of substituted pyridylpyrimidines
WO1995011224A1 (fr) * 1993-10-22 1995-04-27 Abbott Laboratories Procedes de preparation d'un 2,5-diamino-3-hydroxyhexane substitue
US5491253A (en) * 1993-10-22 1996-02-13 Abbott Laboratories Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
US5508409A (en) * 1993-10-22 1996-04-16 Abbott Laboratories Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane
US5616776A (en) * 1993-10-22 1997-04-01 Abbott Laboratories Process for the preparation of a substituted 2.5-diamono-3-hydroxy-hexane
EP0916646A2 (fr) * 1993-10-22 1999-05-19 Abbott Laboratories Préparation d'une 2,5-diamino-3-hydroxyhexane substituée
EP0916646A3 (fr) * 1993-10-22 1999-08-18 Abbott Laboratories Préparation d'une 2,5-diamino-3-hydroxyhexane substituée

Also Published As

Publication number Publication date
NZ227299A (en) 1991-08-27
YU231888A (en) 1990-10-31
PL281863A1 (en) 1990-05-14
YU60590A (en) 1992-05-28
NO885412D0 (no) 1988-12-06
SU1750418A3 (ru) 1992-07-23
ES2033013T3 (es) 1993-03-01
IS3422A7 (is) 1989-06-22
CN1034710A (zh) 1989-08-16
EP0322391B1 (fr) 1992-03-25
PT89272B (pt) 1993-07-30
LV10244A (lv) 1994-10-20
PL161564B1 (pl) 1993-07-30
YU60490A (en) 1992-05-28
PL281864A1 (en) 1990-05-14
DK713088D0 (da) 1988-12-21
EG18654A (en) 1993-08-30
IL88641A0 (en) 1989-07-31
IL88641A (en) 1993-04-04
CN1023478C (zh) 1994-01-12
RU1836331C (ru) 1993-08-23
AU2677588A (en) 1989-06-22
PL161565B1 (pl) 1993-07-30
JPH02240A (ja) 1990-01-05
PL156473B1 (pl) 1992-03-31
IE883785L (en) 1989-06-21
MY104117A (en) 1993-12-31
GR3004617T3 (fr) 1993-04-28
AU611978B2 (en) 1991-06-27
KR890009848A (ko) 1989-08-04
ATE73993T1 (de) 1992-04-15
FI885905A (fi) 1989-06-22
PL276562A1 (en) 1990-02-19
HUT54100A (en) 1991-01-28
NO169837B (no) 1992-05-04
PT89272A (pt) 1989-12-29
NO169837C (no) 1992-08-12
IS1556B (is) 1994-10-05
DK713088A (da) 1989-06-22
HU204765B (en) 1992-02-28
DE3869583D1 (de) 1992-04-30
IE61133B1 (en) 1994-10-05
NO885412L (no) 1989-06-22

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